Largest real-world study of third dose of COVID-19 vaccine effectiveness

The Clalit Research Institute, in collaboration with researchers from Harvard University, analyzed one of the world’s largest integrated health record databases to examine the effectiveness of the third dose of the Pfizer/BioNTech BNT162B2 vaccine against the Delta variant of SARS-CoV-2. The study provides the largest peer-reviewed evaluation of the effectiveness of a third “booster” dose of a COVID-19 vaccine in a nationwide mass-vaccination setting. The study was conducted in Israel, an early global leader in third-dose COVID-19 vaccination rates. 
    
Many countries are currently experiencing a resurgence of SARS-CoV-2 infections despite hitherto successful vaccination campaigns. This may be due to the greater infectiousness of the delta (B.1.617.2) variant of SARS-CoV-2, and to waning immunity of vaccines administered months earlier. In the face of the current resurgence, several countries are planning to administer a third booster dose of mRNA COVID-19 vaccine. 

This study suggests that a third vaccine dose is effective in reducing severe COVID-19-related outcomes compared to individuals who have received two vaccine doses at least 5 months ago. It is the first to estimate the effectiveness of a third dose of an mRNA COVID-19 vaccine—BNT162b2 specifically—against severe outcomes with adjustment for various possible confounders, including comorbidities and behavioral factors. The study’s large size also allows a more precise assessment of the vaccine’s effectiveness across different time periods, different subpopulations (by sex, age and number of comorbidities), and different severe outcomes (which are rarer and thus require greater sample size). A recent clinical trial conducted by BioNTech included a smaller sample size and did not estimate the third-dose’s effects for more severe outcomes.

The study took place from July 30, 2021 through Sept 23, 2021, coinciding with Israel’s fourth wave of coronavirus infection and illness, during which the Delta (B.1.617.2) variant was the dominant strain in the country for new infections (with very few exceptions). 

Researchers reviewed data from 728,321 individuals aged 12 or above who had received the third dose of the BNT162b2 vaccine. These individuals were carefully matched 1:1 with 728,321 individuals who had received only two shots of the BNT162b2 vaccine at least five months prior. The matching was based on an extensive set of demographic, geographic and health-related attributes associated with risk of infection, risk of severe disease, health status and health seeking behavior. Individuals were assigned to each group dynamically based on their changing vaccination status (198,476 individuals moved from the unvaccinated cohort into the vaccinated cohort during the study). Multiple analyses were conducted to ensure that the estimated vaccine effectiveness was robust to potential biases. The study included a total of over 12,000,000 person-days of follow-up. 

The results show that, compared with individuals who received only two doses five months prior, individuals who received three doses of the vaccine (7 days or more after the third dose) had 93% lower risk of COVID-19-related hospitalization, 92% lower risk of severe COVID-19 disease, and 81% lower risk of COVID-19-related death. Vaccine effectiveness was found to be similar for different sexes, age groups (ages 40-69 and 70+) and number of comorbidities. 

The study also included a population-level analysis which found that infection rates began to drop for each age group 7-10 days after that age group became eligible for the third dose.

The research was conducted by Dr. Noam Barda, Dr. Noa Dagan, Prof. Cyrille Cohen, and Prof. Ran Balicer from the Clalit Research Institute, as well as Prof. Miguel Hernán and Prof. Marc Lipsitch of the Harvard T.H. Chan School of Public Health, Professor Isaac S. Kohane of Harvard Medical School, and Prof. Ben Reis of Boston Children’s Hospital and Harvard Medical School.

“The extensive nationwide rollout of Israel’s third-dose ‘booster’ COVID-19 vaccination campaign provided the Clalit Research Institute with a unique opportunity to assess, through its rich and comprehensive digital datasets, the effectiveness of the third dose in a real-world setting against the less common but severe complications of COVID-19” said Prof. Ran Balicer, senior author of the study, Director of the Clalit Research Institute and Chief Innovation Officer for Clalit. “These results show convincingly that the third dose of the vaccine is highly effective against severe COVID-19-related outcomes in different age groups and population subgroups, one week after the third dose. These data should facilitate informed policy decision-making,” added Prof. Balicer, who also serves as Chairman of Israel's National Expert Advisory Team on COVID-19 response.

Prof. Ben Reis, Director of the Predictive Medicine Group at the Boston Children’s Hospital Computational Health Informatics Program and Harvard Medical School, said, “To date, one of the main drivers of vaccine hesitancy has been a lack of information regarding the effectiveness of the vaccine. This careful epidemiological study provides reliable information on third-dose vaccine effectiveness, which we hope will be helpful to those who have not yet decided about vaccination with a third dose.” 

Prof. Miguel Hernán, Director of the CAUSALab and Professor at the Harvard T.H. Chan School of Public Health, said, “This research is a perfect example of how randomized trials and observational healthcare databases complement each other. The trial of the Pfizer/BioNTech vaccine provided compelling evidence of its effectiveness to prevent symptomatic infection, but the estimates for severe disease and specific age groups were too imprecise. This analysis of Clalit’s high-quality database emulates the design of the original trial, uses its findings as a benchmark, and expands upon them to confirm the vaccine’s effectiveness in adolescents. This combination of evidence from randomized trials and observational studies is a model for efficient medical research, something which is especially important in COVID times.”

Prof. Marc Lipsitch, Director of the Center for Communicable Disease Dynamics and Professor at the Harvard T.H. Chan School of Public Health, said, “In all studies of vaccine effectiveness, a major challenge is to ensure that those we are comparing to identify the vaccine’s effect are similar in the other characteristics that may predict whether they get infected or ill. This is especially hard in the context of a rapidly growing, age-targeted vaccine campaign. Clalit’s extraordinary database made it possible to design a study that addressed these challenges in a way that provides tremendous confidence in the inferences that come out of the study.”

The research was funded in part by the newly announced Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.

“The strengthening of the scientific collaboration between Harvard and Clalit made possible by the Berkowitz Living Laboratory Collaboration is already bearing fruit and giving us a foretaste of the value of healthcare systems instrumented for research,” said Prof. Isaac Kohane, Chair of the Department of Biomedical Informatics at Harvard Medical School and co-Director of the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration along with Professor Balicer. “Israel offers a unique environment in which to study the vaccine and its effects, and this study is an excellent example of what can be accomplished through such close scientific collaborations.”